New study from our Stem Cell Research Group at Beijing Neurosurgical Institute provides deeper understanding of therapeutic mechanisms of stem cell therapy for stroke in a rat model. This study is published in the August issue of the Journal of Translational Medicine.
Ischemic stroke is a common neurological disorder and is one of the leading causes of casualty worldwide. Current treatments are primarily palliative and are useful to only a minority of patients after stroke. Currently, there is no effective treatment for restoring the neurological functions lost during a stroke.
The ability of neural stem cells (NSC) to differentiate into neural cells has been seen in culture. Given the complexity of both the structure and function of the central nervous system (CNS), it is critical to understand the mechanisms by which transplanted neural cells can replace the damaged cells and interact with healthy host cells in a well-organized manner.
Cell-based therapy might elicit a chaperone effect in the at-risk neural tissue surrounding the lesioned area via the up-regulation of neurotrophic and neuroprotective factors, which help to promote the survival, migration and differentiation of endogenous precursors after stroke.
The relationship between functional improvements in ischemic rats given a neural stem cell (NSC) transplant and the modulation of the class I major histocompatibility complex (MHC) mediated by NSC-derived neurotrophins was investigated, the authors write as background information in the article.
We found a significant increase of nerve growth factor (NGF), brain-derived neurotropic factor (BDNF) and eurotrophin-3 (NT-3) transcripts and nerve growth factor (NGF) proteins in both the neural stem cell (NSC) cultures and the cerebral spinal fluid (CSF) of the rats. The immunochemical staining for major histocompatibility complex (MHC) in brain sections and the enzyme-linked immunosorbent assay of CSF were carried out in sham-operated rats and rats with surgically induced focal cerebral ischemia. These groups were further divided into animals that did and did not receive NGF administration or NSC transplant into the cisterna magna. Our results show an up-regulation of class I MHC in the ischemic rats with NGF and NSC administration. The extent of caspase-III immunoreactivity was comparable among three arms in the ischemic rats.
Motor function – ischemic rats with either NGF injection or neural stem cell transplant.
Analyses of motor function over four weeks of sham-operated normal control rats, ischemic control rats and ischemic rats with either NGF injection or neural stem cell transplant. This suggests that NSC transplant and NGF administration could enhance symptomatic relief.
Immunohistochemical staining of MHC. Reddish-brown immunoreactivity of class I and II MHC were shown in panel A and B, respectively. A representative coronal section of the hippocampus of an ischemic rat brain without injection of NGF or NSC exhibited no positivity of class I MHC (A-i). Intense staining of class I MHC was noted in the cytoplasm of pyramidal neurons in the hippocampus of ischemic rats undergone neural stem cell transplant for four weeks (A-ii). Clusters of cells with class I MHC-positivity were evident in the infarcted brain parenchyma of transplanted rats (A-iii and A-iv). A comparable extent of class II MHC was noted in ischemic rats irrespective of any therapy but unremarkable in normal rat (panel B, top row). Reddish-brown staining of Class II MHC was evident in the infarcted brain parenchyma (B-i), along the meninge (B-ii), areas near the ventricular lining and vascular wall near the hippocampus (B-iv) of transplanted rats. Scale bars: 75 μm
The findings presented here provide further insights into the mechanisms of neural stem cells in the regeneration of the central nervous system. Should the MHC modulation mediated by NSC-derived neurotrophins be elucidated, strategic cellular therapy for neural injuries and neuro-degenerative diseases may be revolutionized, and novel treatment modalities could be developed.
This study was supported in part by the grant reference 30371452 of the National Natural Science Foundation of China.